ARTICLE

disheartening results. Only around one

What has neuroscience third of those in the study recovered fully
on the first antidepressant prescribed
(Trivedi et al., 2006). For psychological
ever done for us? treatments the picture is only a little
better: Cuijpers and colleagues (2014)
found that less than half recovered fully
Jonathan Roiser (winner of the Society’s Spearman Medal 2013) considers the across a variety of commonly used
case of mental health psychotherapies (with evidence-based
treatments such as cognitive behavioural
therapy performing best).
Over the past 25 years the pace of ental health problems exert an In other words, while our standard
progress in neuroscience research
has been extraordinary, with
advances in both understanding
M enormous social and economic
burden. By way of example, the
cost of depression alone to the British
treatments work well for some, they fail
many, resulting in people suffering for
longer than they should. There are
and technology. We might expect economy is over £9 billion annually currently no methods available in
that this would stimulate improved (Thomas & Morris, 2003), and more standard mental health practice that
understanding and treatment of than twice as many people die from can predict, even with modest accuracy,
mental health problems, yet in suicide each year in the UK than are which treatment is going to work for
general this has not been the case. killed on its roads (Office for National which individual. And the many people
In fact, our standard treatment Statistics). These stark figures are for whom treatments fail serve as a
approaches have barely changed in surprising given that depression is reminder that developing better
decades, and still fail many people treatable, with strong evidence supporting interventions remains a priority.
suffering from mental distress. both pharmacological and psychological
Why is there this disconnect interventions.
between knowledge and Why have these social and economic The difficulty in applying
application? And could we be on costs remained so high even as treatments neuroscience research
the brink of an exciting new era have improved? Access to treatment, in The past quarter of a century has
of cooperation between the two particular psychological therapy, has witnessed numerous advances in
disciplines, increasing the increased in recent years (Layard & neuroscience, such as neuroimaging and
effectiveness of existing treatments Clark, 2014), but of course could be non-invasive electrical brain stimulation
and even suggesting new ones? better. And while the stigma associated in humans, and optogenetics in animals
with mental health problems is greatly (the highly selective activation of neurons
reduced from what it was a generation using laser light, see Fenno et al., 2011).
ago (Office for National Statistics), we If we believe that ‘minds are what brains
are still far from the point where public do’ (Minsky, 1988), we might expect this
perceptions of mental health problems to lead to improved treatment of mental
equate to those of physical conditions. health problems. Yet arguably, the only
Why do different people with the same
questions

However, these are not the only important appreciable impact of neuroscience
symptoms respond to different
factors. As mental health practitioners are research on routine mental health practice
treatments?
well aware, even when a person comes has been in the use of animal models to
Why should clinical psychologists care forward for treatment, selecting the right develop new drugs, which has yielded
about understanding symptoms at the treatment pathway is a huge challenge. few new treatments in this field over the
level of the brain? The impressive statistical evidence past decade.
base from treatment trials masks great This disconnect between modern
variability: different treatments work for neuroscience research and mental health
resources

Holmes, E.A., Craske, M.G. & Graybiel, different people (and while this article practice partly reflects the unresolved
A.M. (2014). Psychological treatments: focuses on depression, the same holds for ‘hard’ problem of consciousness: How
A call for mental-health science.
Nature, 511, 287–289. all mental health problems). For example, does the brain generate experience?
a large community-based study of Mapping between activity in neurons or
medication for depression revealed quite circuits and subjective experience remains
references

Craig, A.D. (2009). How do you feel – psychotherapies for major (2011). The development and valence modulates brain functional
now? The anterior insula and human depression in adults on remission, application of optogenetics. Annual abnormalities in depression.
awareness. Nature Reviews recovery and improvement: A meta- Review of Neuroscience 34, 389–412. Neuroscience and Biobehavioural
Neuroscience, 10(1), 59–70. analysis. Journal of Affective Gaynes, B.N., Lloyd, S.W., Lux, L. et al. Reviews, 37(2), 152–163.
Cristea, I.A., Kok, R.N. & Cuijpers, P. Disorders, 159, 118–126. (2014). Repetitive transcranial Holmes, E.A., James, E.L., Kilford, E.J. &
(2015). Efficacy of cognitive bias Drevets, W.C., Price, J.L., Simpson, J.R., magnetic stimulation for treatment- Deeprose, C. (2010). Key steps in
modification interventions in anxiety Jr. et al. (1997). Subgenual prefrontal resistant depression: A systematic developing a cognitive vaccine
and depression: Meta-analysis. cortex abnormalities in mood review and meta-analysis. Journal of against traumatic flashbacks:
British Journal of Psychiatry 206, 7–16. disorders. Nature, 386(6627), Clinical Psychiatry, 75(5), 477–489. Visuospatial Tetris versus verbal pub
Cuijpers, P., Karyotaki, E., Weitz, E. et al. 824–827. Groenewold, N.A., Opmeer, E.M., de quiz. PLoS One, 5, e13706.
(2014). The effects of Fenno, L. Yizhar, O. & Deisseroth, K. Jonge, P. et al. (2013). Emotional Layard, R. & Clark, D.M. (2014). Thrive.

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a huge conceptual, indeed philosophical, different symptoms: one experiencing low be a single mechanism for a descriptive
challenge. Good science (including mood, poor appetite, difficulty sleeping, diagnosis like depression is probably
clinical science) requires reliable worthlessness and suicidal thoughts; the wishful thinking. For this reason, we
measurement, and neuroscience deals other anhedonia, excessive sleep, fatigue, will never be able to diagnose ‘depression’
with what can be measured objectively psychomotor retardation and difficulty with a brain scan; because symptom-
at the level of the brain. In animals, making decisions. There is no obvious based categories probably conflate
neuroscience measurements and reason why these very different clinical clusters of individuals in whom diverse
manipulations can be causally related presentations should correspond to brain processes drive symptoms.
to behaviour, but experience can only be a unitary underlying causal mechanism Moreover, neuroscientific explanations
inferred indirectly; human studies have (meaning here simply the processes deal with continuous measurements,
attempted to link brain function to that give rise to symptoms, regardless and therefore naturally align better with
subjective experience of whether at the spectrum approaches than with
measured using self- psychological or categorical biomedical models. This is
report, but for ethical neuroscientific part of the logic that has motivated the
reasons these studies level). American National Institute of Mental
are largely correlational. However, a Health to move away from funding
More broadly, we lack more fundamental studies based on descriptive categorical
a generally accepted challenge is that diagnoses.
neuroscientific the even the same The argument here is not that mental
explanation of how symptoms could health practitioners should simply ignore
brains make minds be caused by symptoms altogether. Symptoms will
(though there have completely different always be the first pointers towards
been some attempts, mechanisms. Take mechanisms – just as they are in other
e.g. Craig, 2009). the simplistic clinical disciplines. Someone who visits
By contrast, clinical example of a cough. their GP with a cough is not immediately
characterisations of Using a descriptive, subjected to an invasive procedure. But if
mental health problems, approach one could the cough persisted for several months
whether conceptualised define a ‘cough then a doctor might use a diagnostic test
as categorical disorders syndrome’ – cough to help figure out its cause, before
or lying on a spectrum, (cardinal symptom), recommending a treatment. In mental
are based on symptoms In mental health practice the might commonly health practice the symptoms are the
that in many cases only symptoms are the diagnosis co-occur with runny diagnosis (or spectrum), by definition.
exist subjectively. In nose, sore throat, There are no standard diagnostic
other words, mental fatigue, etc. A cough procedures to aid GPs in deciding, for
health practice takes subjective has many potential causes: viral or example, whether a depressed individual
experience as its starting point – there bacterial infection in the lung; asthma; or might be best treated by drugs targeting
is no objective test for low mood, worry even cancer. But these are conditions that the serotonin or noradrenaline systems,
or hallucination. Whether one adopts are defined mechanistically, not according or psychological interventions targeting
a categorical or spectrum view, mental to symptoms. Most importantly they cognitive schemata or avoidance of
health practitioners rely on descriptive require radically different treatments: reinforcing activities, or some
definitions, in which the symptoms antibiotics for bacterial infections; combination of these. And while an
specify the spectrum or diagnosis. steroids for asthma; chemotherapy, experienced psychologist might be able
radiotherapy or even surgery for lung to tailor an intervention such as CBT
cancer. according to her assessment of the factors
Why can’t we diagnose Although the mechanisms driving that triggered and maintain symptoms,
disorders using brain scans? depressive symptoms will be far more trial-and-error in treatment selection is
Mapping symptomatically and complex than those of a cough, this common.
categorically defined mental disorders example serves to highlight the inherent
onto brain circuits is arguably a hopeless limits of a purely symptom-based
task. To start with, consider the clinical diagnostic system, especially when What do we mean by a ‘cause’?
heterogeneity. Two individuals diagnosed considering treatment selection. It also I propose that in order to improve our
with depression could have completely suggests that the notion that there might understanding and treatment of mental

London: Allen Lane. American Journal of Psychiatry, 156(5), serotonin, norepinephrine and Trivedi, M.H., Rush, A.J., Wisniewski, S.R.
Lozano, A.M., Mayberg, H.S., Giacobbe, P. 675–682. dopamine levels in humans. et al. (2006). Evaluation of outcomes
et al. (2008). Subcallosal cingulate Minsky, M. (1988). The society of mind. Molecular Psychiatry, 12(4), 331–359. with citalopram for depression using
gyrus deep brain stimulation for New York: Simon and Schuster. Sroufe, L.A. & Rutter, M. (1984). The measurement-based care in
treatment-resistant depression. Roiser, J.P., Elliott, R. & Sahakian, B.J. domain of developmental STAR*D: Implications for clinical
Biological Psychiatry, 64(6), 461–467. (2012). Cognitive mechanisms of psychopathology. Child Development, practice. American Journal of
Mayberg, H.S., Liotti, M., Brannan, S.K. treatment in depression. 55, 17–29. Psychiatry, 163(1), 28–40.
et al. (1999). Reciprocal limbic- Neuropsychopharmacology, 37(1), Thomas, C.M. & Morris, S. (2003). Cost of
cortical function and negative mood: 117–136. d depression among adults in England
Converging PET findings in Ruhe, H.G., Mason, N.S. & Schene, A.H. in 2000. British Journal of Psychiatry,
depression and normal sadness. (2007). Mood is indirectly related to 183, 514–519.

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 spearman medal

health problems we need to specify the However, ‘cancer’ is

causes of symptoms at the level of the not really a single entity but
organ that generates them: the brain. It instead a cluster of illnesses,
might be claimed that such an approach and modern advances in
is too reductionist, ignoring the complex cancer biology have yielded
psychosocial context in which symptoms more precise (and
develop. In the standard biopsychosocial consequently more useful)
model, brain-based explanations of proximal causes, pinning
mental health problems are usually down the exact genetic
grouped together with other ‘biological’ mutations that drive different
factors, such as genetic or hormonal, and sorts of tumours. Such
as a counterpoint to ‘psychosocial’ causes, findings have raised the
such as interpersonal stress or early life prospect of an era of Serotonin does not usually directly induce activity
experience. But this is a strange division. ‘personalised medicine’ in in neurons
Of course brain function is influenced oncology, as targeted drugs are
by genetics; but it is also profoundly developed for specific mechanisms concepts of equifinality and multifinality
influenced by the environment, (Herceptin being a well-known example). (Sroufe & Rutter, 1984). As in oncology,
particularly the social environment. For tumours driven by the relevant the hope is that better specification of the
To put it another way, brain-based genetic mechanism, treatment with these proximal causes of mental health
explanations of symptoms are neither drugs can be highly effective. However, problems will result in better treatment.
‘biological’ nor ‘psychosocial’, but instead they are ineffective (even detrimental) for
must incorporate both. other types.
If one accepts the philosophical By contrast, distal causes are indirectly Causes of depression
position that all subjective experience related to the mechanisms driving The majority of studies of depression
arises from activity in brain circuits then symptoms, and are useful targets for have focused on distal causes (which
the brain becomes an obvious place to prevention; they are often identified psychologists might consider
search for the mechanisms driving through epidemiology research. Again, ‘underlying’). These include: heritability
symptoms, from uncontrollable elation take the example of lung cancer, which is and genetics; hormonal and immune
to outright despair. Indeed, it could be (distally) caused by cigarette smoking in factors; upbringing and early life
argued that integrating psychological and the majority of cases, though it must be experience; and personality. More
neuroscientific information is the only caused by other factors in people who proximal causes include: various forms
way in which a truly holistic explanation have never smoked. These could be of stress, particularly social; high-level
of mental health problems can be genetic (lung cancer is heritable), other psychological constructs derived from
proposed, as the brain is the interface types of environmental trigger (e.g. radon cognitive theories (e.g. dysfunctional
at which genetic and environmental gas exposure) or some interaction negative schemata); low-level constructs
influences interact to produce thoughts, between the two. Given the such as negative information processing
perceptions, beliefs and feelings. And overwhelming evidence that lung cancer biases (also important in anxiety); and
there is no reason to assume that a brain is (distally) caused by smoking, efforts at disrupted transmission in
mechanism can only be targeted using prevention rightly focus on reducing its neurotransmitter systems such as
a ‘biological’ treatment – psychosocial incidence. However, after a tumour has serotonin.
interventions change the brain too. developed an oncologist must focus on However, none of these factors is
Importantly, this is not to privilege the proximal cause when proposing a specified at the level of activity in brain
neuroscientific models over psychological course of treatment. Of course, there is circuits. Dysfunctional negative schemata
models of symptoms. Each discipline has often some relationship between proximal are internal representations of the
much to learn from the other, since they and distal causes – smokers do tend to environment that are proposed to trigger
address the same questions but in a develop similar tumours. However, two and sustain symptoms – but schemata
complementary fashion, at different levels patients could have cancers with very must themselves be encoded in the brain.
of explanation. Ultimately they require similar proximal causes, requiring the The hypothesis of disrupted serotonin
integration: ‘mindless’ neuroscience and same treatment, even if one is a regular transmission is derived from the effects of
‘brainless’ psychology are both incomplete smoker and the other has never smoked. antidepressant drugs – but serotonin does
explanatory frameworks. In mental health practice, this brings not usually directly induce activity in
A useful notion is to consider to mind the (now largely historical) neurons; instead it modulates ongoing
different types of causes of symptoms distinction between ‘reactive’ versus activity. The proposal that low levels of
lying on a spectrum, the extremes of ‘endogenous’ depression; originally this ‘happy hormone’ somehow directly
which I will term ‘proximal’ and ‘distal’. thought to be distinct sub-types of illness induce depressive symptoms is not well
Proximal causes are directly related to the driven by distinct environmental and supported by available evidence (Ruhe et
mechanisms driving symptoms, and are genetic (distal) causes, and suited to al., 2007), and leaves a large conceptual
useful targets for treatment; they are often different interventions. In fact, this gap in the serotonin hypothesis.
identified through basic science research. classification was unreliable and What of attempts to specify
For example, lung cancer is (proximally) prediction of response to treatment was depression at the level of brain
caused by malfunction in the machinery never shown to be consistent. In other circuits? In the 1990s seminal studies
that regulates cell division. Traditional words, similar distal causes do not demonstrated that regional brain
lung cancer treatments tackle this cause necessarily imply similar proximal metabolism and blood flow (proxies
by removing the malfunctioning cells causes, as has long been recognised in for activity) were altered in depressed
(surgery) or killing them (standard developmental psychopathology where individuals. These identified consistent
chemotherapy and radiotherapy). close parallels can be drawn with the differences between depressed and never-

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depressed individuals in brain structure depressed people before a course of anatomically specific and delivered at
and function in specific parts of the treatment, while they performed simple much lower intensity (with only a tiny
prefrontal cortex. For example, depressed emotion processing tasks. Importantly, risk of seizure). Several high-quality trials
individuals had hyperactivity in the different treatments were used in different have provided convincing evidence that
subgenual anterior cingulate cortex studies: specific medications in some, and depressive symptoms can be reduced
(sgACC: Drevets et al., 1997), which CBT or behavioural activation therapy in through daily DLPFC rTMS (Gaynes et
normalised following recovery (Mayberg others. These treatments were then al., 2014). In America this technique
et al., 1999). Mayberg also showed that administered over several weeks, and has already received Federal Drug
inducing sad mood in non-depressed a final assessment of symptom change Administration approval as a potential
people had the opposite effect of recovery was taken (using standard interviews treatment option in depressed individuals
from depression, increasing sgACC such as the Hamilton Rating Scale for who have not responded to medication.
activity. Subsequent work using Depression), which was related to Neuroscience findings might also
functional magnetic resonance imaging baseline brain activation. stimulate new avenues of research to
(fMRI) demonstrated convincingly that Consistent findings were observed develop innovative psychological
the sgACC forms part of a circuit that across studies, but in different directions treatments. A classic example was the
supports the brain’s processing of basic for psychological and pharmacological development of exposure therapy to
emotional information, suggesting treatments (Roiser et al., 2012). treat phobias, based on the principles
a potential role in generating negative Psychological treatments worked best of extinction derived from behavioural
biases. Dozens of further studies have in individuals with relatively normal neuroscience. More recently, it has been
confirmed robust abnormalities in this baseline sgACC activation during proposed that using visuo-spatial
circuit in depression, especially during negative emotional processing. By distraction to prevent the initial
emotional processing (Groenewold et al., contrast, pharmacological treatments consolidation of memories in the
2013). Taken together, these studies worked best in individuals with abnormal aftermath of traumatic exposure could
support the notion that negative affective baseline sgACC activation. Importantly, act as a ‘cognitive vaccine’, stopping the
perception and experience in depressed this was independent of baseline severity. development of flashbacks in the first
people are caused (proximally) by Identifying the regions that operate place (Holmes et al., 2010). Finally,
disrupted function in the brain circuits abnormally in depressed individuals cognitive bias modification has been
that support normal emotional has also led to the development of new developed with the aim of targeting low-
processing. approaches that intervene directly at the level negative emotion processing directly,
level of brain circuits, both invasive and but this requires more investigation with
non-invasive. Deep brain stimulation high-quality trials (Cristea et al., 2015).
Interesting, but useful? (DBS) is a surgical technique that
The information provided by involves applying continuous electrical
neuroscience may be interesting, but is stimulation directly to a localised brain A new era?
it useful? It is up to neuroscientists to region through an implanted electrode, At first glance the question posed in my
convince mental health practitioners that like a pacemaker for the brain. title, echoing the famous scene in Monty
their discoveries can make a difference to Importantly, and unlike earlier Python’s The Life of Brian, may have
intervention, and explain what form such psychosurgical approaches, DBS does provoked a similar sentiment to that of
application might take. Despite the not involve destruction of brain tissue, the character Reg, who cannot
conceptual problems in mapping and the stimulator can be removed if it acknowledge that the Romans have
symptoms onto brain circuits, such efforts is ineffective. Initially developed to treat delivered any civic improvements at all.
have already provided some surprising Parkinson’s disease, it was first attempted Although modern neuroscience research
progress in the treatment of depression. in depression about a decade ago, has, as yet, had minimal impact on
One conclusion that can be drawn targeting the sgACC. An open-label mental health practice, we are on the
from neuroscience studies is to confirm trial of DBS in chronically depressed brink of an exciting period.
that ‘depression’ is indeed mechanistically individuals produced encouraging In the short term the most important
heterogeneous, and not a single entity at results, with approximately 50 per cent effect will be to encourage us to change
the level of the brain. Despite the categorised as responders to treatment the way we think about symptoms,
statistical evidence for group differences, after 12 months (Lozano et al., 2008). focusing on proximal causes at the level
even the most robust brain-imaging However, these impressive preliminary of the brain and how these relate to
abnormality in depression (reduced results need to be replicated in psychological processes. Longer term, the
sgACC volume) cannot differentiate randomised controlled trials. Similar hope is that by recognising mechanistic
between depressed and never-depressed trials have shown that DBS to other brain heterogeneity we will develop better
individuals reliably. If one were to regions can also treat chronic obsessive- classification systems, new approaches to
calculate a ‘normal range’ of sgACC compulsive symptoms. intervention, and further tools to enable
volumes in a non-depressed population, Clearly, surgical interventions will practitioners to choose the right
the majority of depressed individuals only ever be used in the most extreme treatment for the right individual.
would lie within it. cases. However, non-invasive methods
But might we be able to exploit this of direct brain stimulation have also been
variability in brain structure and function developed, in particular using repetitive Jonathan Roiser
among individuals with the same transcranial magnetic stimulation (rTMS) is at the Institute of
diagnosis, in order to improve treatment to target the dorsolateral part of the Cognitive Neuroscience,
selection? A series of studies using similar prefrontal cortex (DLPFC), which is University College London
designs (reviewed in Roiser et al., 2012) extensively connected with the sgACC. [Link]@[Link]
has yielded some intriguing preliminary rTMS is completely different to [Link]/jonroiser
results. These scanned the brains of electroconvulsive therapy – it is

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